Improving translatability of preclinical studies for neuromuscular disorders: lessons from the TREAT-NMD Advisory Committee for Therapeutics (TACT)

Abstract

Clinical trials for rare neuromuscular diseases imply, among other investments, a high emotional burden for the whole disease community. Translation of data from preclinical studies to justify any clinical trial must be carefully pondered in order to minimize the risk of clinical trial withdrawal or failure. A rigorous distinction between proofof-concept and preclinical efficacy studies using animal models is key to support the rationale of a clinical trial involving patients. This Review evaluates the experience accumulated by the TREAT-NMD Advisory Committee for Therapeutics, which provides detailed constructive feedback on clinical proposals for neuromuscular diseases submitted by researchers in both academia and industry, and emphasizes that a timely critical review of preclinical efficacy data from animal models, including biomarkers for specific diseases, combined with adherence to existing guidelines and standard protocols, can significantly help to de-risk clinical programs and prevent disappointments and costly engagement.

Using the concept of “deserved trust” to strengthen the value and integrity of biomedical research

“…[It also] allow[s] the comparison of pathological phenotypes with the human disease, and [provides] insight into the underlying reasons for differences at varying levels of complexity, [thereby] allowing the identification of protective pathways in animals that could be enhanced in humans." (Willmann et al 2020) Preclinical studies both develop and test "novel therapeutics, including small molecules, biologics, gene modifiers and cell therapies", as well as inform "optimal dosing regime[s] and route [s]." (Willmann et al 2020) In short, these studies help determine which investigational treatment modalities migrate out of the laboratory into human trials.…”

“…(Willmann et al 2020) Preclinical studies both develop and test "novel therapeutics, including small molecules, biologics, gene modifiers and cell therapies", as well as inform "optimal dosing regime[s] and route [s]." (Willmann et al 2020) In short, these studies help determine which investigational treatment modalities migrate out of the laboratory into human trials.…”

“…It notes it is asking taxpayers to trust it to use their tax dollars to support its research to, for example, identify "protective pathways in animals that could be enhanced in humans." (Willmann et al 2020) Since progress toward this goal will depend upon the rigor of its research and the accuracy and robustness of its research reports, by asking question 2 about the accountability methods and practices that are in place, as well as how well they work, the team realizes that, in order to assure the quality of its work, it cannot just wait to learn whether a journal will publish its results, given how weak a quality assurance mechanism peer review is. Thus, it is led to question 3 asking whether any additional steps should be taken and subsequently consider how it can buttress its work.…”

Do we really know how many clinical trials are conducted ethically? Why research ethics committee review practices need to be strengthened and initial steps we could take to strengthen them

“…An advisory committee for the development of certain new therapeutics has recently reminded us how central these studies are to clinical translation efforts. 12 It should be noted that many are deeply sceptical about the value of animal studies to clinical translation, given how vast the differences can be between species. 13 Whether one shares this scepticism or not, these are the studies RECs must rely on to support inferences committee members make regarding the nature and potential of both benefits and risks in early trials.…”

“…Finally, a 2020 review of preclinical studies related to neuromuscular disorders reports that almost 30% had deficient use of control groups, blinding or randomisation. 12 Such studies help to explain the findings of a recent survey of biomedical researchers showing that the vast majority of respondents believe there is a 'reproducibility crisis' in biomedical research. 24 One might question the direct relevance of these aggregate findings to RECs since they have to review individual trials, not aggregate challenges of preclinical research generally.…”